It is generally thought that steroid hormones exert their physiological influence by regulating transcriptional activities. Very recently, however, steroids that exhibit their activities rapidly without acting on genes have become widely known, but this cannot be explained by the above theory. Evidence of this rapid action of steroids has been shown for every steroid in many species and tissues. Examples include the rapid action of aldosterone on lymphocytes and vascular smooth muscle (Wehling, M. (1995) Cardiovasc. Res. 29(2), 167-171), vitamin D3 on epithelial cells, progesterone on sperm (Revelli, A.; Modotti, M.; Piffaretti-Yanez, A.; Massobrio, M.; and Balerna, M. (1994) Hum Reprod 9 (5), 760-766), neurosteroids on neurons, and estrogen on blood vessels. The signal recognition and transduction mechanisms of these activities are currently being studied. As a result, it is now becoming clear that the signal recognition and transduction system resembles cascade systems of membrane receptors and the second messengers, such as those of catecholamines and peptide hormones, since many of the activities depend on phospholipase C, phosphoinositide turnover, intracellular pH, intracellular calcium, protein kinase C, tyrosine kinases, etc., (Baran, D. T. (1994) J Cell Biochem 56 (3), 303-306; de Boland, A. R. and Nemere, I. (1992) J Cell Biochem 49 (1), 32-36). Although the physiological or pathological relevance is not clear, it has been presumed that the rapid action of steroids can also be observed in vivo in the cardiovascular system, the central nervous system, and the reproductive system. It was expected that these receptors would be cloned soon and that the relationship between the rapid action of steroids and their clinical effects would be clarified (Wehling, M. (1997) Annu Rev Physiol 59, 365-393; and Wehling, M. (1995) J Mol Med 73 (9), 439-447).
In recent years, the progesterone membrane binding protein (PMBP), a membrane binding type that differs from usual steroid hormone receptors of the intranuclear transcription regulation type, was finally cloned for the first time from a pig (Falkenstein, E.; Meyer, C.; Eisen, C.; Scriba, P. C.; and Wehling, M. (1996) Biochem Biophys Res Commun 229 (1), 86-89). This protein was purified from the microsome fraction, has a hydrophobic region near its N terminus, and shows no homology to existing steroid receptors. To date, a putative human homologue of PMBP, the “putative progesterone binding protein gene” (LOCUS, HSPROGBIN; accession number, Acc. Y12711), and a putative rat homologue, “25Dx” (LOCUS, RNU63315; accession number, Acc. U63315), have been isolated. The pig PMBP has been well characterized, and it has been reported to bind not only to progesterone but also to corticosterone, cortisol, promegestone, and testosterone (Meyer C. (1996) Eur. J. Biochem. 239, 726-731).
The discovery of these membrane-bound steroid hormone binding proteins suggests the existence of a mechanism in the organism for regulating hormone action that differs from the one for the receptors involved in the intranuclear transcription regulation. Therefore, it should be possible to develop novel drugs that distinguish the affinities or biological activities of the membrane-bound steroid hormone binding proteins from those of the intranuclear transcription regulation type receptors using the membrane-bound steroid hormone binding proteins.